Acute and Chronic Afferent Engagement: Sympathetic and End Organ Responses

这是由位于宾夕法尼亚州好时的宾夕法尼亚州立大学医学院的{4}名调查人员向NHLBI重新提交的项目项目赠款。所有的研究人员都是高生产率的科学家。所有项目负责人都是协作型的，所有人都将从这个计划中受益匪浅。我们认为这项应用符合PPG的标准，因为：1)有一个统一的主题，即外周动脉疾病(PAD)加重自主神经反射反应。将使用两种肢体缺血模型：a)人类受试者的PAD(项目1和4)；以及b)大鼠的后肢动脉闭塞(项目2和3)}；2)项目之间存在概念上的协同，将导致心血管生理学和病理生理学方面的重要进展；3)该项目具有广泛的目标，可以在第一个5年的资助期内实现；以及4)所提出的许多想法和概念都是项目负责人之前合作的直接结果。辛诺威博士将担任PPG项目主管(PD)。他拥有丰富的科学和管理经验，自1996年以来担任宾夕法尼亚州立大学综合临床研究中心(GCRC)的PD，自2004年以来担任PPG的PD。在项目1中，Sinoway博士将研究运动加压反射(EPR)在PAD患者肌肉活动过程中调节血压的作用。}他将研究氧化应激在改变PAD患者的反射效应中所起的作用。在项目2中，李博士将研究后肢动脉闭塞(大鼠模型)是否会导致背根神经节(DRG)神经元中P2X、TRPV1和ASIC通道的上调。李博士还将研究神经生长因子(NGF)在这一反应中所起的作用。在项目3中，考夫曼博士将检查第三组和第四组肌肉传入放电(在后肢动脉闭塞模型的大鼠收缩期间)。在项目4中，Leuenberger博士将研究间歇性低氧在改变交感神经反射和血管扩张剂反应性方面所起的作用，间歇性低氧是一种强有力的氧化应激，在正常人和那些以氧化应激为特征的疾病(包括PAD)的患者中扮演着重要角色。提出了两个核心：1)核心A将是行政核心；2)核心B将是人类生理核心。

This is a resubmission of a program project grant to the NHLBI by {four} investigators located within the College of Medicine of the Pennsylvania State University in Hershey, Pennsylvania. All investigators are highly productive scientists. All project leaders are collaborative and all will greatly benefit from this program. We believe this application fulfills the criteria for a PPG because: 1) there is a unifying theme namely that {peripheral arterial disease (PAD) accentuates autonomic reflex responses. Two models of limb ischemia will be employed: a) PAD in human subjects (Projects 1 and 4); and b) hindlimb arterial occlusion in rats (Projects 2 and 3)}; 2) conceptual synergy exists between the projects that will lead to important advances in cardiovascular physiology and pathophysiology; 3) this PPG has broadly defined goals that can be accomplished within the first 5 year funding period; and 4) many of the ideas and concepts proposed are a direct result of previous collaborations between the project leaders. Dr. Sinoway will be the PPG Program Director (PD). He has substantial scientific and administrative experience, serving as the PD of the Penn State General Clinical Research Center (GCRC) since 1996, and PD of a PPG since 2004. In Project 1, Dr. Sinoway will examine the role the exercise pressor reflex (EPR) {plays in regulating blood pressure during muscular activity in patients with PAD.} He will examine the role oxidative stress plays in altering reflex effects in PAD patients. In Project 2, Dr. Li will determine if hindlimb arterial occlusion (rat model) leads to upregulation of P2X, TRPV1 and ASIC channels in dorsal root ganglion (DRG) neurons. Dr. Li will also examine the role nerve growth factor (NGF) plays in this response. In Project 3, Dr. Kaufman will examine group III and IV muscle afferent discharge {during contraction in rats with the hindlimb arterial occlusion model.} In Project 4, Dr. Leuenberger will examine the role intermittent hypoxia, a potent oxidative stress, plays in altering sympathetic reflexes and vasodilator responsiveness in {normal humans and those with diseases characterized by oxidative stress including PAD. Two cores are proposed: 1) Core A will be administrative; and 2) Core B will be a human physiology core.